U.S. patent number 6,858,747 [Application Number 10/819,910] was granted by the patent office on 2005-02-22 for process to prepare, 1,4-dihydropyridine intermediates and derivatives thereof.
This patent grant is currently assigned to Apotex Pharmachem Inc.. Invention is credited to Daqing Che, Bhaskar Reddy Guntoori, K. S. Keshava Murthy.
United States Patent |
6,858,747 |
Che , et al. |
February 22, 2005 |
**Please see images for:
( Certificate of Correction ) ** |
Process to prepare, 1,4-dihydropyridine intermediates and
derivatives thereof
Abstract
An improved catalyst is disclosed for a process involving the
preparation of benzylidene intermediates useful in the preparation
of 1,4-dihydropyridine compounds and derivatives thereof useful as
medicines such as for example felodipine. This is accomplished by
the condensation of an aldehyde and an acetoacetate in the presence
of a novel catalyst system that includes a pyridyl carboxylic acid
and a secondary amine. It has been found that through the use of
the present invention the purity and yield of the desired isomer of
the benzylidene intermediate can be maximized, thus avoiding the
requirement of additional purification steps. The use of these
intermediates can then be further reacted to form the required
dihydropyridines, again having a very high purity and yield
compared with the prior art.
Inventors: |
Che; Daqing (Brantford,
CA), Guntoori; Bhaskar Reddy (Brantford,
CA), Murthy; K. S. Keshava (Ancaster, CA) |
Assignee: |
Apotex Pharmachem Inc.
(Brantford, CA)
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Family
ID: |
33102846 |
Appl.
No.: |
10/819,910 |
Filed: |
April 8, 2004 |
Foreign Application Priority Data
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Apr 14, 2003 [CA] |
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2425561 |
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Current U.S.
Class: |
560/53; 546/249;
546/321; 560/21; 560/51 |
Current CPC
Class: |
C07D
211/90 (20130101) |
Current International
Class: |
C07D
211/00 (20060101); C07D 211/90 (20060101); C07C
069/79 (); C07C 205/00 () |
Field of
Search: |
;560/23,51,53
;546/249,321 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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549753 |
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Dec 1985 |
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ES |
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WO 98/07698 |
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Jul 1997 |
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WO |
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Other References
Cope, Arthur C., Condensation Reactions. I. The Condensation of
Ketones with Cyanoacetic Esters and the Mechanism of the
Knoevenagel Reaction, Journal of the American Chemical Society,
1937, vol. 59, pp. 2327-2330. .
Fener, Chen et al., Synthesis of Calcium Antagonist. III. Synthesis
of Felodipine, 1995, vol. 7, No. 2, pp. 154-157..
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Primary Examiner: Killos; Paul J.
Attorney, Agent or Firm: Sinden; Kitt Hughes; Ivor M.
Sarkis; Marcelo K.
Claims
What is claimed is:
1. A process for the manufacture of a benzylidene intermediate of
formula ##STR14##
wherein R.sub.1 is C.sub.1 to C.sub.12 alkyl which is optionally
substituted by a C.sub.1 -C.sub.4 alkoxyl, a trifluroromethyl or
(C.sub.6 H.sub.5 CH.sub.2)(CH.sub.3)N and X and Y are independently
selected from the group consisting of H, C.sub.1 to C.sub.6 alkyl,
C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylaryl, halo,
aryl, substituted aryl, and nitro, comprising the condensation
reaction of an aldehyde of formula ##STR15##
with an acetoacetate of formula ##STR16##
in the presence of catalytic amounts of a pyridyl carboxylic acid
of formula ##STR17##
and a secondary amine.
2. The process of claim 1 wherein the secondary amine is of formula
where R.sub.3 and R.sub.4 are independently C.sub.1 -C.sub.7 alkyl
or aralkyl.
3. The process of claim 1 wherein the secondary amine is of formula
##STR18##
where n=0, 1, 2, 3.
4. The process of claim 1 wherein the secondary amine is
piperidine.
5. The process of claim 1 wherein the pyridyl carboxylic acid is
picolinic acid.
6. The process of any of claims 1 to 5 further comprising the
reaction of said benzylidene intermediate with a substituted
enamine of formula ##STR19##
where R.sub.2 is C.sub.1 to C.sub.12 alkyl which is optionally
substituted by a C.sub.1 -C.sub.4 alkoxyl, a trifluroromethyl or
(C.sub.6 H.sub.5 CH.sub.2)(CH.sub.3)N and R.sub.2 is not the same
as R.sub.1 wherein the dihydropyridine compound of formula
##STR20##
is formed.
7. A process for the preparation of a benzylidene intermediate of
any of claims 1, 2, 3, 4 or 5 wherein X=Cl, Y=Cl and R.sub.1 is
selected from the group consisting of methyl or ethyl.
8. A process for the preparation of a benzylidene intermediate of
any of claims 1, 2, 3, 4 or 5 wherein X=NO.sub.2, Y=H and R.sub.1
is selected from the group consisting of methyl or ethyl.
9. A process for the preparation of felodipine comprising: (a) the
condensation reaction of an aldehyde of formula ##STR21## with an
acetoacetate of formula ##STR22## in the presence of catalytic
amounts of a pyridyl carboxylic acid of formula ##STR23## and a
secondary amine; and (b) the reaction of the resulting product with
an enamine of formula ##STR24## wherein R.sub.1 and R.sub.2 are
methyl and ethyl respectively or ethyl and methyl respectively.
10. The process of claim 9 wherein the secondary amine is of
formula
wherein R.sub.3 and R.sub.4 are each independently C.sub.1 -C.sub.7
alkyl or aralkyl.
11. The process of claim 9 wherein the secondary amine is of
formula ##STR25##
where n=0, 1, 2 or 3.
12. The process of claim 9 wherein the secondary amine is
piperidine.
13. The process of claim 9 wherein the pyridyl carboxylic acid is
picolinic acid.
14. A process for the preparation of nitrendipine comprising: (a)
the condensation reaction of an aldehyde of formula ##STR26## with
an acetoacetate of formula ##STR27## in the presence of catalytic
amounts of a pyridyl carboxylic acid of formula ##STR28## and a
secondary amine; and (b) the reaction of the resulting product with
an enamine of formula ##STR29## wherein R.sub.1 and R.sub.2 are
methyl and ethyl respectively or ethyl and methyl respectively.
15. The process of claim 14 wherein the secondary amine is of
formula
wherein R.sub.3 and R.sub.4 are each independently C.sub.1 -C.sub.7
alkyl or aralkyl.
16. The process of claim 14 wherein the secondary amine is of
formula ##STR30##
where n=0, 1, 2 or 3.
17. The process of claim 14 wherein the secondary amine is
piperidine.
18. The process of claim 14 wherein the pyridyl carboxylic acid is
picolinic acid.
19. The process of any of claims 1, 9 or 14 wherein one of the
reactions is performed in at least one alcoholic solvent.
20. The process of claim 19 wherein the alcoholic solvent is
isopropanol.
21. The process of claim 6 wherein the benzylamidine intermediate
is isolated prior to the reaction with the enamine.
Description
FIELD OF THE INVENTION
This invention relates generally to the preparation of
intermediates useful in the preparation of 1,4-dihydropyridines and
derivatives thereof, more particularly to the preparation of
intermediates useful in the preparation of felodipine and
nitrendipine.
BACKGROUND OF THE INVENTION
Felodipine and nitrendipine, 1 and 2, represent effective medicines
useful for the treatment of hypertension and as muscle relaxant
drugs. They belong to a class of medicines collectively known as
dihydropyridines. ##STR1##
The preparation of felodipine (ethyl methyl
4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine
dicarboxylate) and related compounds typically involves a multistep
protocol as depicted in Scheme 1. ##STR2##
The acidic- and base-catalyzed condensation of benzaldehyde with an
alkyl acetoacetate to form a key benzylidene intermediate of
formula 4 is known. However, it is also well understood in the art
that the performance of this condensation is very sensitive to the
chemical nature of both base and acid. In particular, when basic
catalysis is used, the benzylidene can be formed at a low
temperature, but then reacts further with another molecule of the
alkyl acetoacetate to form the bis-adduct (6, Scheme 2) as an
impurity. This disadvantage is further compounded for the
intermediate used in the preparation of felodipine since the
requisite benzaldehyde component is 2,3-dichlorobenzaldehyde. When
the resulting dihydropyridine molecule is made in the presence of
these impurities, the chlorine atoms on the aromatic ring make the
carbon atom of the aldehyde more electron deficient relative to
benzaldehyde, further favouring the formation of the undesired
bis-adduct 6. When acid is used as catalyst for this condensation,
for instance as described in U.S. Pat. No. 5,310,917, a mixture of
aldol by-products can also be formed. ##STR3##
The use of piperidinium acetate as catalyst by Arthur C. Cope
(Journal of the American Chemical Society, 1937, 59, 2327-2330)
represents a landmark for making benzylidene compounds. For
example, U.S. Pat. No. 4,600,778 disclosed a process for making
nitrendipine and felodipine using this catalytic system in an
alcoholic solvent. Novel catalytic systems, which purportedly
overcome some of the deficiencies in the synthetic procedures
disclosed in U.S. Pat. No. 4,600,778, are described in U.S. Pat.
No. 5,977,369. However, although the benzylidene intermediate could
be obtained as a mixture composed of two isomers, the yield still
was only about 60% thereby making it undesirable for commercial
production. Summarizing, the major disadvantages with the disclosed
processes for the preparation of dihydropyridine compounds,
particularly felodipine, from benzylidene intermediate processes of
the prior art, include: 1. Formation of symmetrical diesters
(dimethyl and diethyl, 7 and 8, respectively, Scheme 2) byproducts,
which are very difficult to remove from the product. 2. Extractive
workup for isolation of the desired product. 3. Purification by
recrystallization requiring increased manufacturing time and
solvent costs. 4. Low overall yield.
Therefore, a catalytic system combining an optimal balance of base
and acid properties, which would provide the benzylidine
intermediates in high yield and with a minimum number of
side-products, was required.
It is accordingly an objective of the present invention to provide
such a novel, simple and efficient process for the manufacture of
benzylidene intermediates useful in the preparation of
dihydropyridine compounds and, such as the dihydropyridine
molecule, felodipine that overcomes the deficiencies in the prior
art.
SUMMARY OF THE INVENTION
The present invention relates broadly to the preparation of
benzylidene intermediates useful in the preparation of
dihydropyridine compounds and derivatives thereof, and also the use
of the intermediates formed by the process of the present invention
to prepare dihydropyridine compounds useful as medicines.
In the broadest sense it is an object of the invention to provide
for a process for the manufacture of a benzylidene intermediate of
formula I: ##STR4##
wherein R.sub.1 is C.sub.1 to C.sub.12 alkyl which is optionally
substituted by a C.sub.1 -C.sub.4 alkoxyl, a trifluroromethyl or
(C.sub.6 H.sub.5 CH.sub.2)(CH.sub.3)N and X and Y are independently
selected from the group consisting of H, C.sub.1 to C.sub.6 alkyl,
C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylaryl, halo,
aryl, substituted aryl, and nitro, comprising the condensation of
an aldehyde of formula II: ##STR5##
with an acetoacetate of formula III ##STR6##
in the presence of a pyridyl carboxylic acid of formula IV
##STR7##
and a secondary amine of formula V
where R.sub.3 and R.sub.4 are independently C.sub.1 -C.sub.7 alkyl
or aralkyl, or a secondary amine of formula VI Formula VI
##STR8##
wherein n=0, 1, 2, 3.
Additionally it is a further object of the invention to provide for
the further reacting of the benzylidene intermediate of formula I
with a substituted enamine of formula VII ##STR9##
where R.sub.2 is C.sub.1 to C.sub.12 alkyl which is optionally
substituted by a C.sub.1 -C.sub.4 alkoxyl, a trifluroromethyl or
(C.sub.6 H.sub.5 CH.sub.2)(CH.sub.3)N and R.sub.2 is not the same
as R.sub.1 to form the dihydropyridine compound useful as a
medicine of formula VIII ##STR10##
In one instance, the intermediates prepared can be used to obtain
relatively high purity and yield of felodipine or nitrendipine with
little additional purification steps.
One can prepare a benzylidene intermediate useful in the
preparation of the medicine felodipine. Thus,
2,3-dichlorobenzaldehyde is condensed with methyl acetoacetate in
the presence of a novel catalyst system forming the benzylidene
intermediate, 4a ##STR11##
This benzylidene intermediate prepared using the novel catalyst
system can further be reacted with ethyl aminocrotonate to provide
felodipine.
In another instance, the process to prepare a nitrendipine
benzylidene intermediate follows a similar process except that
3-nitrobenzaldehyde is used instead of
2,3-dichlorobenzaldehyde.
Surprisingly and unexpectedly, we have discovered that the
resulting dihydropyridine, for example felodipine could be isolated
in very high purity (>99.5%) directly from the reaction mixture
if the benzylidene intermediate 4 could be isolated in highly pure
form (>99%). In another aspect of the present invention, we have
found a novel catalyst system through which the benzylidene
intermediate could be prepared in high purity and high yield.
Thus, 2,3-dichlorobenzaldehyde reacts with methyl acetoacetate in
the presence of a catalytic amount of pyridyl carboxylic acid and
piperidine in an alcoholic solvent at a temperature of
30-60.degree. C. for 5-10 hours. After cooling to 10-40.degree. C.,
the reaction mixture is maintained for a period of 3-10 hours. The
resulting solid is filtered and washed with alcohol solvent
(corrected yield 80-85%). The damp solid is used directly in the
next step. In the second step, the benzylidene intermediate reacts
with ethyl aminocrotonate in an alcoholic solvent under reflux
temperature for 10-30 hours. The solvent is removed and an
anti-solvent is added. The product is then filtered and washed with
an additional amount of solvent thereby furnishing felodipine in a
yield of about 80-95% from the benzylidene intermediate and a HPLC
purity of 99.6%. Furthermore, the product meets the high purity
specifications required for pharmaceutical active ingredients
without necessitating the need for further purification.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the invention relates to the convenient preparation
of intermediates useful in the preparation of dihydropyridines
useful as medicines, for example, felodipine. This invention also
covers the generic preparation of other intermediate for similar
members of the dipine class of antihypertensives and muscle
relaxants. Examples that this invention is applicable to include,
but is not limited to, dihydropyridines such as nitrendipine,
nisoldipine, nimodipine, nilvadipine, arandipine, lacidipine,
manidipine, isradipine, amlodipine, cronidipine, diperdipine, and
furaldipine. It is well understood by one skilled in the art that
analogous procedures can be used to manufacture these
dihydropyridines intermediates and the resulting dihydropyridine
molecules.
The synthetic scheme depicted in Scheme 1 illustrates the reaction
sequence for the preparation of felodipine using the intermediate
formed by the process of the present invention. This scheme is for
exemplary purposes and the application to other dihydropyridines
such as those mentioned above will be readily apparent by one
skilled in the art.
Step I
One embodiment of the present invention involves the synthesis of
the intermediate methyl benzylidene 4a.
Surprisingly and unexpectedly, we have found that a catalytic
system comprised of a pyridyl carboxylic acid, of formula IV
(Scheme 3), in combination with a secondary amine, of formula V, or
VI (Scheme 3), serves this purpose very well. The basic centre on
the pyridine ring plays an unexpectedly important role in this
system. Examples of the pyridyl carboxylic acid include picolinic
acid, nicotinic acid and 4-pyridyl carboxylic acid, most preferably
picolinic acid. Examples of secondary amine of formula V include
amines where R.sub.3 and R.sub.4 are C.sub.1 -C.sub.7 alkyl,
aralkyl. Examples of secondary amines of formula VI include amines
where n=0, 1, 2, and 3, most preferably piperidine. When systems
such as this are employed as catalyst, the condensation reaction
proceeds cleanly and the benzylidene intermediate precipitates out
upon cooling and without distillation of the solvent. ##STR12##
Also of importance, catalysts of the aforementioned type favour the
equilibrium to the less soluble isomer relative to the more soluble
isomer (Scheme 4) thereby permitting convenient isolation of the
less soluble isomer by filtration and in high purity (>99% as a
single isomer) and high yield (>80%). The advantages of being
able to obtain the benzylidene in pure form will become apparent in
the preparation of felodipine in step II and are demonstrated by
comparing felodipine prepared in Example 1 versus Comparative
Example 2. ##STR13##
Step II
The benzylidene intermediate of step I is condensed with a suitable
substituted enamine, such as ethyl aminocrotonate, in a refluxing
alcoholic solvent, preferably isopropanol. In one embodiment of the
present invention, the methyl benzylidene intermediate formed in
step I is preferably isolated and reacted with ethyl
aminocrotonate. Preferably the methyl benzylidene intermediate is
suspended in isopropanol and ethyl aminocrotonate is added, and the
contents refluxed until the reaction is completed.
Contrary to the teachings of the prior art and a clear advantage in
this present invention, the felodipine reaction is not sensitive to
the amount of ethyl aminocrotonate charged during the second step.
The amount of ethyl aminocrotonate could be 0.8-2.0 equivalent of
benzylidene, preferably 1.1-1.4 equivalents. We have found that if
the benzylidene is clean (>99% as single isomer), the product
could be isolated in high purity (>99.5%) and high yield
(>87% based on benzylidene). The reaction could be run under
reflux for 8-30 hours, preferably 15-20 hours, in an alcohol
solvent, preferably isopropanol.
The product is isolated conveniently by removing a portion of the
isopropanol and adding an anti-solvent, such as heptanes, and then
filtration. The product is dried and is pharmaceutically acceptable
without further purification.
The following examples are illustrative of the invention and are
not to be considered limiting the scope of the invention in any
manner.
EXAMPLES
Example 1
Preparation of Felodipine
Step I
To a solution of 2,3-dichlorobenzaldehyde (101.0 g, 0.58 mol) in
isopropanol (450 mL) is added picolinic acid (3.5 g, 29 mmol),
piperidine (2.4 g, 29 mmol) and methyl acetoacetate (86.3 g, 0.74
mol). The solution is stirred at 40-45.degree. C. for 6 h, cooled
to room temperature and the solid is filtered and washed with
isopropanol. The damp cake is dried to yield 125.9 g (80%)
benzylidene 4a as white solid.
Step II
To a suspension of benzylidene from step I (125.9 g, 0.46 mol) in
isopropanol (600 mL) is added ethyl aminocrotonate (71.5 g, 0.55
mol). The reaction mixture is heated under reflux for 12 hours.
Isopropanol is distilled and heptanes (400 mL) is added. The
resulting solid is filtered and washed with heptanes. After drying
151.9 g (86%) felodipine is obtained as pale yellow solid with a
purity of 99.6% (a/a). Melting range: 142-144.degree. C.
(corrected). .sup.1 H NMR (300 MHz, CDCl.sub.3): .delta.=7.30 (1H,
dd); 7.24 (1H, dd); 7.06 (1H, at); 5.84 (1H, s); 5.46 (1H, s); 4.07
(2H, q); 3.61 (3H, s); 2.31 (3H, s); 2.29 (3H, s); 1.18 (3H, t);
.sup.13 C NMR (75 MHz, CDCl.sub.3): .delta.=168.1; 167.6; 148.3;
144.5; 144.4; 132.9; 131.2; 129.9; 128.4; 127.2; 104.0; 103.6;
60.0; 51.1; 38.8; 19.7; 19.6; 14.5.
Comparative Example 2
Preparation of Felodipine Without Isolation of the Benzylidene
Intermediate
To a solution of 2,3-dichlorobenzaldehyde (8.76 g, 0.05 mol) in
isopropanol (80 mL) is added picolinic acid (0.65 g, 5.4 mmol),
piperidine (0.45 g, 5.4 mmol) and methyl acetoacetate (86.3 g, 0.06
mol). The solution is stirred at 40-45.degree. C. for 6 h, and then
isopropanol is distilled under vacuum. The residue is dissolved in
ethyl acetate (80 mL) and washed with water (60 mL). Ethyl acetate
is then removed under vacuum. To the residue is added ethyl
aminocrotonate (7.74 g, 0.06 mol) and isopropanol (60 mL). The
mixture is heated under reflux for 4 hours. Isopropanol is
distilled and heptanes (60 mL) is added. The resulting solid is
filtered and washed with heptanes. After drying 12.7 g (66%)
felodipine is obtained as pale yellow solid with a purity of 94.4%
(diethyl and dimethyl have a concentration of 2.02% and 3.38%
(a/a), respectively).
Example 3
Preparation of Nitrendipine
Step I
To a solution of 3-nitrobenzaldehyde (75.6 g, 0.50 mol) in
isopropanol (250 mL) is added picolinic acid (4.74 g, 39 mmol),
piperidine (3.54 g, 39 mmol) and methyl acetoacetate (75.4 g, 0.65
mol). The solution is stirred at 40-45.degree. C. for 6 h, cooled
to room temperature and the solid is filtered and washed with
isopropanol. The damp cake is dried to yield 108.3 g (87%)
benzylidene as pale yellow solid.
Step II
To a suspension of benzylidene (108.3 g, 0.43 mol) in isopropanol
(400 mL) is added ethyl aminocrotonate (67.3 g, 0.52 mol). The
reaction mixture is heated under reflux for 10 hours, cooled to
room temperature and the solid is filtered and washed with
isopropanol. After drying 140.1 g (89%) nitrendipine is obtained as
pale yellow solid.
.sup.1 H NMR (300 MHz, DMSO-d.sub.6): .delta.=9.06 (1H, s);
8.05-7.97 (2H, m); 7.66-7.52 (2H, m); 4.99 (1H, s); 4.04 (2H, q);
3.55 (3H, s); 2.31 (3H, s); 2.30 (3H, s); 1.15 (3H, t); .sup.13 C
NMR (75 MHz, DMSO-D.sub.6): .delta.=167.0; 166.5; 150.1; 147.6;
146.6; 146.4; 134.1; 129.6; 121.7; 121.1; 101.1; 100.8; 59.2; 50.8;
39.1; 18.3; 18.2; 14.1.
* * * * *